High turnover of types III and VI collagen in progressive idiopathic pulmonary fibrosis

Abstract

Background and objective Prediction of idiopathic pulmonary fibrosis (IPF) progression is vital for the choice and timing of treatment and patient follow‐up. This could potentially be achieved by prognostic blood biomarkers of extracellular matrix (ECM) remodelling. Methods Neoepitope biomarkers of types III and VI collagen turnover (C3M, C6M, PRO‐C3 and PRO‐C6) were measured in 185 patients with newly diagnosed IPF. Disease severity at baseline and progression over 6 months was assessed by lung function tests and 6‐min walk tests. All‐cause mortality was assessed over a 3‐year follow‐up period. Results High baseline levels of C3M, C6M, PRO‐C3 and PRO‐C6 were associated with more advanced disease at the time of diagnosis. Baseline levels of C6M and PRO‐C3 were also associated with mortality over 3 years of follow‐up (hazard ratio [HR]: 2.3, 95% CI: 1.3–3.9, p = 0.002 and HR: 1.8, 95% CI: 1.1–3.0, p = 0.03). Patients with several increased biomarkers at baseline, representing a high ECM remodelling phenotype, had more advanced disease at baseline, higher risk of progression or death at 6 months (OR: 1.4, 95% CI: 1.1–1.8, p = 0.002) and higher mortality over 3 years of follow‐up (HR: 2.4, 95% CI: 1.3–4.5, p = 0.007). Conclusion Blood biomarkers of types III and VI collagen turnover, assessed at the time of diagnosis, are associated with several indices of disease severity, short‐term progression and long‐term mortality. These biomarkers can help to identify patients with a high ECM remodelling phenotype at high risk of disease progression and death.

Turnover of type I and III collagen predicts progression of idiopathic pulmonary fibrosis

“…Since our data suggest that patients with a higher baseline type I and III collagen turnover have a higher risk of disease progression, it would be interesting to make a direct comparison of C1M and PRO-C3 with the above-mentioned biomarkers to verify if they could perform better. Interestingly, we have recently shown that degradation of type III collagen (C3M) was related to disease severity at the time of diagnosis [28]. However, in the present analyses, it was not related to increased risk of progression, indicating that C3M is more associated with disease severity rather than being a prognostic biomarker in this population.…”

“…This may be explained by the fact that C1M is generated with different matrix metalloproteinases (MMP-2, -9 and -13) and C3M is only generated with MMP-9, what may clarify the reason why C1M is related to progression and C3M is not. Degradation of type I collagen (C1M) and formation of type III and VI collagen (PRO-C3 and PRO-C6) have consistently been shown to be promising biomarkers for disease progression and these biomarkers may reflect and predict fibrotic changes in the lung [15,16,28]. We hope future studies will validate our findings.…”

“…IPF results from increased levels of interstitial collagens, changing the architecture of the airspaces in the lungs [25][26][27], and elevated type I and III collagen turnover has been shown to be related to disease progression in IPF patients [15,16]. Recently, we demonstrated that type III collagen degradation (C3M) and formation (PRO-C3) are associated with disease severity at baseline and high PRO-C3 levels were related to survival [28]. In the current study, we investigated whether biomarkers of type I and III collagen turnover measured at baseline could be used to predict risk of disease progression within 12 months.…”

LPA1 antagonist BMS-986020 changes collagen dynamics and exerts antifibrotic effects in vitro and in patients with idiopathic pulmonary fibrosis

“…High baseline serum concentrations of collagen formation biomarkers, PRO-C3 and PRO-C6, were also associated with more rapid disease progression (≥ 10% FVC decline or death) [ 9 ]. The latter findings were consistent with results from the PFBIO cohort, a real-world cohort of Danish patients with mild IPF (n = 185, baseline mean [SD] percent predicted FVC 89.7% [19.3]) [ 10 ].…”

“…Neoepitope biomarkers can be used to assess ECM remodeling in fibrotic conditions such as IPF [ 6 , 7 ]; these neoepitope biomarkers measure newly formed epitopes that may be generated by removal of collagen propeptides (reflecting protein formation) or by specific protease-mediated cleavage of mature proteins (reflecting protein degradation). Multiple longitudinal studies have demonstrated that elevated serum levels of these biomarkers are associated with poor prognosis in IPF [ 8 – 10 ].…”